Abstract Eosinophilic Esophagitis (EoE) is a chronic, allergic gastrointestinal disorder marked by esophageal eosinophilia persisting from childhood into adulthood. One of the central questions in the EoE field, and allergy in general, is to understand why individuals develop certain manifestations of allergic disease, such as EoE. We have recently found that in addition to allergic sensitization genetic risk factors, EoE susceptibility is linked to a genetic locus at 2p23, encoding the CAPN14 gene and calpain-14 protein. This genetic linkage has been replicated in multiple cohorts, as well as a recent independent study, adding credence to the importance of the 2p23 genetic linkage. Calpain-14 has not been previously studied outside of our recent new dataset; however, known substrates for other members of the classical calpains include inflammatory mediators relevant for allergic responses. We identified CAPN14 as dynamically up-regulated as a function of EoE disease activity and genetic haplotype, as well as after exposure of epithelial cells to IL-13. In preliminary studies, we have identified a set of intronic and intragenic genetic variants that are most likely to be causal for increased EoE risk. We have also generated data substantiating a regulatory role for calpain-14 in both disease induction and repair. Using these results, we propose a set of aims designed to test our central hypothesis that the development of EoE is mediated by genetic risk factors that include the interplay of generalized atopy susceptibility loci (11q13/5q22) and an EoE esophageal response involving CAPN14. We will test this hypothesis by focusing on functional mechanisms that account for the genotype-dependent regulation of CAPN14 expression (Aim 1) and the downstream targets and regulatory role of calpain-14 (Aim 2). Based upon our hypothesis that calpain-14 functions in the context of IL-13-mediated inflammation, we will assess the increased clinical predictive utility of genetic variants at 2p23 through the statistical consideration of diagnosis with allergic rhinitis, asthma, or atopic dermatitis and other key atopy associated genetic loci (Aim 3). These experiments are timely, as they address an unmet medical need as outlined by a recent NIH workshop (see Bochner et al JACI; PMCID: PMC3432981 and PA-15-027). Through a set of three aims testing complementary hypotheses, we present an opportunity to dissect an important disease and make real progress towards a global understanding of the functional genomic, biochemical, inflammatory, and interactive mechanisms that increase risk of EoE through 2p23 and calpain-14.